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Review
. 2014 Aug 28:6:25-64.
doi: 10.4137/PMC.S14459. eCollection 2014.

Antibiotics and bacterial resistance in the 21st century

Richard J Fair  1 , Yitzhak Tor  2
Affiliations
Review

Antibiotics and bacterial resistance in the 21st century

Richard J Fair et al. Perspect Medicin Chem. .

Abstract

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Keywords: antibiotic resistance mechanisms; antibiotics; drug-resistant bacteria; novel antibiotic targets.

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Figures

Figure 1
Figure 1
Deaths caused by select bacteria in the United States.
Figure 2
Figure 2
Timeline of first clinical introduction of antibiotic classes. Notes: Classes targeting the cell wall or membrane are highlighted in blue. Classes targeting the ribosome are highlighted in green.
Figure 3
Figure 3
Sulfonamides and trimethoprim (3). Note: The sulfonamide moiety is highlighted in blue.
Figure 4
Figure 4
Penicillin subclass β-lactams. Note: The β-lactam moiety is highlighted in blue.
Figure 5
Figure 5
Cephalosporin subclass β-lactams. Note: The β-lactam moiety is highlighted in blue.
Figure 6
Figure 6
Carbapenem subclass β-lactams. Note: The β-lactam moiety is highlighted in blue.
Figure 7
Figure 7
Monobactam subclass β-lactams. Note: The β-lactam is moiety highlighted in blue.
Figure 8
Figure 8
β-lactamase inhibitors. Note: The β-lactam moiety is highlighted in blue.
Figure 9
Figure 9
Aminoglycosides. Note: The 2-DOS ring is highlighted in blue.
Figure 10
Figure 10
Chloramphenicol (30).
Figure 11
Figure 11
Macrolides. Note: The cladinose ring is highlighted in blue, deosamine in green.
Figure 12
Figure 12
Ketolides. Note: The deosamine ring is highlighted in green.
Figure 13
Figure 13
Tetracyclines and the glycylcycline, tigecycline (46).
Figure 14
Figure 14
Rifamycins, including the newly approved rifaximin (51).
Figure 15
Figure 15
Vancomycin (52) glycopeptide and derivatives.
Figure 16
Figure 16
Teicoplanin (55) glycopeptide and derivative.
Figure 17
Figure 17
The lipoglycodepsipeptide ramoplanin (57).
Figure 18
Figure 18
Select first through fourth generation quinolones.
Figure 19
Figure 19
Class A and B streptogramins.
Figure 20
Figure 20
Polymyxins including preclinical polymyxin B analog, NAB739.
Figure 21
Figure 21
Oxazolidinones. Note: The oxazolidinone rings are highlighted in blue.
Figure 22
Figure 22
Daptomycin (79) and surotomycin (80), a lipopeptide in clinical development.
Figure 23
Figure 23
Retapmulin (81) and the BC-3781 (82), a pleuromutilin in clinical development.
Figure 24
Figure 24
The macrolactone fidaxomicin (83).
Figure 25
Figure 25
The diarylquinoline bedaquiline (84).
Figure 26
Figure 26
Potential combination therapies. Notes: Cadazolid (85), a quinolone (blue) and oxazolidinone (red) combination. TD-1792 (86), a glycopeptide (blue) and β-lactam (red) combination.
Figure 27
Figure 27
Antibiotic candidates with novel targets. Notes: MBX-1162 (87) is a double stranded nucleic acid groove binder. SB-RA-5001 (88) and PC190723 (89) target FtsZ. BB-83698 (90), LBM415 (91), and GSK1322322 (92) target peptide deformylase. Abyssomycin C (93) blocks p-aminobenzoic acid formation in the tetrahydrofolate biosynthetic pathway. Platensimycin (94) targets FabF and platencin (95) is a dual FabF / FabH inhibitor. GSK2251052 (96) inhibits leucyl-tRNA synthetase.
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